Solid compositions of triglycerides and uses thereof

ABSTRACT

The present invention includes solid compositions of triglycerides with one or more fatty acids, such as triheptanoin and glycerol phenylbutyrate, and therapeutic use thereof. The solid compositions can be prepared by spray-drying or other processes.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Continuation of U.S. application Ser. No.14/419,601, filed on Feb. 4, 2015, which is a U.S. National StageApplication of International Application No. PCT/US2014/065693, filed onNov. 14, 2014, which claims the benefit of U.S. Provisional PatentApplication No. 61/904,369 filed Nov. 14, 2013, the contents of each ofwhich are herein incorporated by reference in their entirety for allpurposes.

FIELD OF THE INVENTION

The present invention relates to solid compositions of triglycerideswith one or more fatty acids, such as triheptanoin and glycerolphenylbutyrate, and the therapeutic use thereof.

BACKGROUND OF THE INVENTION

Current dosage form of the triglycerides drug, e.g., triheptanoin, is aliquid with the consistency of oil. Several problems are associated withthe liquid dosage form due to its physical and physiological properties.First, the liquid dosage forms, such as oil, are difficult to beadministered due to low miscibility with food or drinks. Second, the oilformulations are difficult to be handled, carried, and dispensed.Furthermore, upon administration, the oil composition is hydrolyzed andreleased rapidly in the stomach leading to gastric upset, gastricretention, and likely gastrin-related stomach spasm and emesis. Inaddition, the oil formulations can cause diarrhea by reforming oildroplets and causing a mineral-oil like excess lubrication. Uponrepetitive administration of the oil, some patients experience gastricstress which causes vomiting and/or diarrhea. Thus, the tolerability inthe oil form can be a dose-limiting toxicity or lead to adverse effects,and the reduced administrable dose would negatively impact the treatmenteffect for a fatty acid oxidation disorder or deficiency (FAOD); adultpolyglucosan body disease; a mitochondrial fat oxidation defect; aglycogen storage disease; a mitochondrial myopathy; glucose transportertype 1 (GLUT1) deficiency syndrome, or other related diseases.

SUMMARY OF THE INVENTION

Among other things, the present invention is directed to a solidcomposition comprising an ester derived from a polyol and one or morefatty acids as an active ingredient, and a solid substance. To give anexample of the ester, triglycerides with one or more fatty acids aresuitable for use in accordance with the present invention.

In one aspect, the present invention provides a solid compositioncomprising triglycerides with one or more odd-numbered carbon fattyacids as an active ingredient and a solid substance; wherein the activeingredient has purity greater than 98% and the one or more odd-numberedcarbon fatty acids are selected from the group consisting of C5, C7, C9,C11, C13, C15, and any combinations thereof; and the solid compositioncomprises at least about 50% by weight the triglycerides. The presentinvention also provides a solid composition comprising a plurality ofsolid particles, each particle comprising triglycerides with one or moreodd-numbered carbon fatty acids as an active ingredient adsorbed onto asolid substance; wherein the active ingredient has purity greater than98% and the one or more odd-numbered carbon fatty acids are selectedfrom the group consisting of C5, C7, C9, C11, C13, C15, and anycombinations thereof; and the solid composition comprises at least about50% by weight the triglycerides.

In another aspect, the present invention provides a solid compositioncomprising triglycerides with one or more phenylalkanoic acids and/orphenylalkenoic acids as an active ingredient and a solid substance;wherein the active ingredient has purity greater than 95% and the solidcomposition comprises at least about 50% by weight the triglycerides.The present invention also provides a solid composition comprising aplurality of solid particles, each particle comprising triglycerideswith one or more phenylalkanoic acids and/or phenylalkenoic acids as anactive ingredient adsorbed onto a solid substance; wherein the activeingredient has purity greater than 95% and the solid compositioncomprises at least about 50% by weight the triglycerides.

In some embodiments, the solid composition comprises at least about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, or about 90% of the active ingredient by weight of the composition.

In some embodiments, the solid substance includes a solid carrier. Thesolid carrier can be a fumed silica. Additionally or alternatively, thesolid carrier can be selected from the group consisting of SiO₂, TiO₂,Al₂O₃, zeolites, Cab-O-Sil, and combinations thereof.

The solid substance can further comprise one or more sustained releasepolymers.

In some embodiments, the sustained release polymer is a film-forming,water insoluble polymer. The film-forming, water insoluble polymer canbe selected from the group consisting of ethylcellulose, celluloseacetate, cellulose propionate (lower, medium or higher molecularweight), cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate phthalate, cellulose triacetate, poly(methylmethacrylate), poly(ethyl methacrylate), poly(butyl methacrylate),poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutylacrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) lowdensity, poly(ethylene) high density, poly(propylene), poly(ethyleneoxide), poly(ethylene terephthalate), poly(vinyl isobutyl ether),poly(vinyl acetate), poly(vinyl chloride) or polyurethane, or mixturesthereof. In one embodiment, the film-forming, water insoluble polymer iscellulose acetate.

In some embodiments, the sustained release polymer comprises one or morepH dependent polymers. The pH dependent polymer can be selected from agroup consisting of a methyl acrylate-methacrylic acid copolymer, acellulose acetate succinate, a hydroxy propyl methyl cellulosephthalate, a hydroxy propyl methyl cellulose acetate succinate(hypromellose acetate succinate), a polyvinyl acetate phthalate (PVAP),a methyl methacrylate-methacrylic acid copolymer, alginate and stearicacid, and any combinations thereof.

In some embodiments, the solid composition comprises, by weight of thecomposition, about 50% to about 80% of the active ingredient; about 10%to about 30% of the solid carrier; and about 10% to about 30% of thesustained release polymer. In some embodiments, the active ingredient,the solid carrier, and the sustained release polymer are in a weightratio of about 2:1:1.

The solid composition in accordance with the present invention can be inform of a powder. In some embodiments, the powder comprises particleshaving an average diameter of less than about 10 micron. The particlescan have an average diameter of less than about 9 microns, less thanabout 8 microns, less than about 7 microns, less than about 6 microns,less than about 5 microns, less than about 4 microns, less than about 3microns, less than about 2 microns, less than about 1000 nm, less thanabout 900 run, less than about 800 run, less than about 700 nm, lessthan about 600 nm, less than about 500 nm, less than about 400 nm, lessthan about 300 nm, less than about 290 nm, less than about 280 nm, lessthan about 270 nm, less than about 260 nm, less than about 250 nm, lessthan about 240 nm, less than about 230 nm, less than about 220 nm, lessthan about 210 nm, less than about 200 nm, less than about 190 nm, lessthan about 180 nm, less than about 170 nm, less than about 160 nm, lessthan about 150 nm, less than about 140 nm, less than about 130 nm, lessthan about 120 nm, less than about 110 nm, less than about 100 nm, lessthan about 90 nm, less than about 80 nm, less than about 70 nm, lessthan about 60 nm, less than about 50 nm, less than about 40 nm, lessthan about 30 nm, less than about 20 nm, less than about 10 nm, lessthan about 9 nm, less than about 8 nm, less than about 7 nm, less thanabout 6 nm, or less than about 5 nm.

In some embodiments, the solid substance has a surface area of at least20 m²/g.

In some embodiments, the solid particles are formed by spray drying aspray suspension comprising the triglycerides with one or moreodd-numbered carbon fatty acids as an active ingredient and the solidsubstance.

The solid composition in accordance with the present invention caninclude triglycerides with seven carbon fatty acids. In someembodiments, the solid composition further comprises triglycerides withone or more odd-numbered carbon fatty acids selected from the groupconsisting of C5, C9, C11, C13, C15, and any combinations thereof.

In some embodiments, the triglycerides is a triheptanoin oil comprisinggreater than about 98% pure glycerol triheptanoate as an activeingredient. The triheptanoin oil can comprise less than 1% w/w of anon-C7 triglyceride or a combination of non-C7 triglycerides.

The solid composition in accordance with the present invention canfurther include a pharmaceutically acceptable excipient.

In some embodiments, the solid composition includes an active ingredientthat has purity greater than 97% after about four weeks of exposure toabout 25° C. at about 60% relative humidity when package in a sealedcontainer. In some embodiments, the solid composition has a watercontent of no more than 1.0% by weight after about four weeks ofexposure to about 25° C. at about 60% relative humidity when package ina sealed container. In some embodiments, the solid composition includesan active ingredient that has purity greater than 98% after about fourweeks of exposure to about 25° C. at about 60% relative humidity whenpackage in a sealed container. In some embodiments, the solidcomposition has a water content of no more than 0.5% by weight afterabout four weeks of exposure to about 25° C. at about 60% relativehumidity when package in a sealed container. In some embodiments, thesolid composition includes an active ingredient that has purity greaterthan 99% after about four weeks of exposure to about 25° C. at about 60%relative humidity when package in a sealed container. In someembodiments, the solid composition has a water content of no more than0.35% by weight after about four weeks of exposure to about 25° C. atabout 60% relative humidity when package in a sealed container.

In some embodiments, the solid composition includes an active ingredientthat has purity greater than 97% after about four weeks of exposure toabout 40° C. at about 75% relative humidity when package in a sealedcontainer. In some embodiments, the solid composition has a watercontent of no more than 1.0% by weight after about four weeks ofexposure to 40° C. at about 75% relative humidity when package in asealed container. In some embodiments, the solid composition includes anactive ingredient that has purity greater than 98% after about fourweeks of exposure to about 40° C. at about 75% relative humidity whenpackage in a sealed container. In some embodiments, the solidcomposition has a water content of no more than 0.5% by weight afterabout four weeks of exposure to 40° C. at about 75% relative humiditywhen package in a sealed container. In some embodiments, the solidcomposition includes an active ingredient that has purity greater than99% after about four weeks of exposure to about 40° C. at about 75%relative humidity when package in a sealed container. In someembodiments, the solid composition has a water content of no more than0.45% by weight after about four weeks of exposure to 40° C. at about75% relative humidity when package in a sealed container.

The present invention provides a method of treating a disease, disorder,or condition in a subject comprising orally administering to the subjecta therapeutically effective amount of a solid composition in accordancewith the present invention, wherein the disease, disorder, or conditionis selected from any one or more of the following: a fatty acidoxidation disorder or deficiency; adult polyglucosan body disease; amitochondrial fat oxidation defect (e.g., relating to carnitinepalmitoyl transferase I, carnitine palmitoyl transferase II, carnitineacylcarnitine translocase, very long chain acyl-CoA dehydrogenase,trifunctional protein, long chain hydroxyacyl-CoA dehydrogenase,multiple acyl-CoA dehydrogenase, short chain acyl CoA dehydrogenase,alpha glucosidase, brancher enzyme, debrancher enzyme, myophosphorylase,or phosphofructokinase); a glycogen storage disease (e.g., glycogenstorage disease Type II); glucose transporter type 1 (GLUT1) deficiencysyndrome; and a mitochondrial myopathy.

Also provided is a method of treating a disease, disorder, or conditionin a subject comprising orally administering to the subject atherapeutically effective amount of a solid composition in accordancewith the present invention, wherein the disease, disorder, or conditionis selected from any one or more of the following: urea cycle disorders(UCD) and hepatic encephalopathy (HE).

In some embodiments, the solid composition is co-administered with afood, drink, or comestible composition.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is the metabolite pharmacokinetics (PK) profile of triheptanoinand heptanoate following triheptanoin oil dosing on Day 1 in male andfemale mini-pigs combined.

FIG. 2 is the metabolite PK profile of triheptanoin and heptanoatefollowing triheptanoin powder-ER dosing on Day 1 in male and femalemini-pigs combined.

FIG. 3 is the metabolite PK profile of triheptanoin and heptanoatefollowing triheptanoin powder dosing on Day 1 in male and femalemini-pigs combined.

FIG. 4 is the metabolite PK profile up to 48 hours (left) or 8 hours(right) of heptanoate following triheptanoin oil, powder and powder-ERdosing on Day 1 in male and female mini-pigs combined. Heptanoate (C7)metabolite PK following triheptanoin oil, powder and powder-ER dosing onDay 1 in male and female mini-pigs combined.

FIG. 5 is the metabolite PK profile of B-hydroxybutyric acid (C4-OH) andB-hydroxyvaleric acid (C5-OH) following triheptanoin powder-ER dosing onDay 1 in male and female mini-pigs combined.

FIG. 6 is the metabolite PK profile of B-hydroxybutyric acid (C4-OH) andB-hydroxyvaleric acid (C5-OH) following triheptanoin oil dosing on Day 1in male and female mini-pigs combined.

FIG. 7 is the metabolite PK profile of B-hydroxybutyric acid (C4-OH) andB-hydroxyvaleric acid (C5-OH) following triheptanoin powder dosing onDay 1 in male and female mini-pigs combined.

FIG. 8 is the metabolite PK profile up to 48 hours (left) or 8 hours(right) of B-hydroxybutyric acid (C4-OH) following triheptanoin oil,powder and powder-ER dosing on Day 1 in male and female mini-pigscombined. B-Hydroxybutyric acid (C4-OH) metabolite PK followingtriheptanoin oil, powder and powder-ER dosing on Day 1 in male andfemale mini-pigs combined.

FIG. 9 is the metabolite PK profile up to 48 hours (left) or 8 hours(right) of B-hydroxyvaleric acid (C5-OH) following triheptanoin oil,powder and powder-ER dosing on Day 1 in male and female mini-pigscombined. B-Hydroxyvaleric acid (C5-OH) metabolite PK followingtriheptanoin oil, powder and powder-ER dosing on Day 1 in male andfemale mini-pigs combined.

FIG. 10 is the metabolite PK profile of aspartate following triheptanoinpowder-ER dosing on Day 1 in male and female mini-pigs combined.

FIG. 11 is the metabolite PK profile of aspartate following triheptanoinoil dosing on Day 1 in male and female mini-pigs combined.

FIG. 12 is the metabolite PK profile of aspartate following triheptanoinpowder dosing on Day 1 in male and female mini-pigs combined.

FIG. 13 is the metabolite PK profile of glutamate following triheptanoinpowder-ER dosing on Day 1 in male and female mini-pigs combined.

FIG. 14 is the metabolite PK profile of glutamate following triheptanoinoil dosing on Day 1 in male and female mini-pigs combined.

FIG. 15 is the metabolite PK profile of glutamate following triheptanoinpowder dosing on Day 1 in male and female mini-pigs combined.

FIG. 16 is the metabolite PK profile of pimelic acid,3-hydroxypropionate and propionyl glycine following triheptanoinpowder-ER dosing on Day 1 in male and female mini-pigs combined.

FIG. 17 is the metabolite PK profile of pimelic acid,3-hydroxypropionate and propionyl glycine following triheptanoin oildosing on Day 1 in male and female mini-pigs combined.

FIG. 18 is the metabolite PK profile of pimelic acid,3-hydroxypropionate and propionyl glycine following triheptanoin powderdosing on Day 1 in male and female mini-pigs combined.

FIG. 19 is the profile of average energy and alternative metabolitesfollowing triheptanoin powder-ER dosing on Day 1 in male and femalemini-pigs combined.

FIG. 20 is the profile of average energy and alternative metabolitesfollowing triheptanoin oil dosing on Day 1 in male and female mini-pigscombined.

FIG. 21 is the profile of average energy and alternative metabolitesfollowing triheptanoin powder dosing on Day 1 in male and femalemini-pigs combined.

FIG. 22 is the metabolite PK profile of heptanoic acid followingtriheptanoin oil dosing on Day 1 and Day 7 in male and female mini-pigscombined.

FIG. 23 is the metabolite PK profile of C4-hydroxy followingtriheptanoin oil, powder and powder-ER dosing on Day 1 and Day 7 in maleand female mini-pigs combined.

FIG. 24 is the metabolite PK profile of C5-hydroxy followingtriheptanoin oil, powder and powder-ER dosing on Day 1 and Day 7 in maleand female mini-pigs combined.

FIG. 25 is the metabolite PK profile of aspartic acid followingtriheptanoin oil, powder and powder-ER dosing on Day 1 and Day 7 in maleand female mini-pigs combined.

FIG. 26 is the metabolite PK profile of glutamic acid followingtriheptanoin oil, powder and powder-ER dosing on Day 1 and Day 7 in maleand female mini-pigs combined.

FIG. 27 is the metabolite PK profile of pimelic acid followingtriheptanoin oil, powder and powder-ER dosing on Day 1 and Day 7 in maleand female mini-pigs combined.

FIG. 28 is the metabolite PK profile of 3-hydroxypropionate followingtriheptanoin oil, powder and powder-ER dosing on Day 1 and Day 7 in maleand female mini-pigs combined.

FIG. 29 is the metabolite PK profile of propionyl glycine followingtriheptanoin powder and powder-ER dosing on Day 1 and Day 7 in male andfemale mini-pigs combined.

FIG. 30 is the sum of all metabolite PK profiles following triheptanoinoil, powder and powder-ER dosing on Day 1 and Day 7 in male and femalemini-pigs combined.

FIG. 31 is the metabolite PK profile of C4-hydroxy followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil dosing) on Day 1 and Day 7 in male and female mini-pigs.

FIG. 32 is the metabolite PK profile of C5-hydroxy followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil dosing) on Day 1 and Day 7 in male and female mini-pigs.

FIG. 33 is the metabolite PK profile of heptanoic acid followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil closing) on Day 1 and Day 7 in male and female mini-pigs.

FIG. 34 is the metabolite PK profile of pimelic acid followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil dosing) on Day 1 and Day 7 in male and female mini-pigs.

FIG. 35 is the metabolite PK profile of glutaric acid followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil dosing) on Day 1 and Day 7 in male and female mini-pigs.

FIG. 36 is the metabolite PK profile of aspartic acid followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil dosing) on Day 1 and Day 7 in male and female mini-pigs.

FIG. 37 is the metabolite PK profile of glutamic acid followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil dosing) on Day 1 and Day 7 in male and female mini-pigs.

FIG. 38 is the metabolite PK profile of alanine following triheptanoinpowder and powder-ER dosing (fold change relative to the oil dosing) onDay 1 and Day 7 in male and female mini-pigs.

FIG. 39 is the metabolite PK profile of 3-hydroxypropionate followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil dosing) on Day 1 and Day 7 in male and female mini-pigs.

FIG. 40 is the metabolite PK profile of propionyl glycine followingtriheptanoin powder and powder-ER dosing (fold change relative to theoil dosing) on Day 1 and Day 7 in male and female mini-pigs.

DETAILED DESCRIPTION OF THE INVENTION

A solid composition in accordance with the present invention comprisesan ester derived from a polyol and one or more fatty acids as an activeingredient, and a solid substance. The term “polyol” denotes an alcoholcontaining two or more hydroxyl groups. Examples of polyols include, butare not limited to, diol (e.g., ethylene glycol, propylene glycol, andresorcinol), triol (e.g., glycerol and ethane-1,1,2-triol), tetraol(e.g., pentaerythritol), and sugar alcohols (e.g., maltitol, sorbitol,xylitol, and erythritol,). In one embodiment, the polyol is glycerol.

In one embodiment, the present solid compositions are particularlyuseful as pharmaceutical formulation with both improved physicalproperties and physiological properties. In one embodiment, the solidcompositions are easier to be administered because they are misciblewith food, drink, or other comestible compositions with ease. In anotherembodiment, the solid compositions, such as powder or granule dosageforms, are more portable and easier to handle and dispense duringregular daily use or while traveling. In another embodiment, the solidcompositions are more stable during storage and easier to be handled andtransported during manufacture and commercialization. In anotherembodiment, the solid compositions may have masked taste and improvedose tolerability and reduce side effects. In another embodiment, thesolid compositions, e.g., the powder dosage forms, have delayed releasecharacteristics in the stomach, with limited gastric upset, distress, orspasms. In another embodiment, the solid compositions do not causediarrhea from the oil leading to excess lubrication of the GI tractthrough its delayed release and stabilized physical presence allowingbetter and more complete digestion during passage in thegastrointestinal tract. In another embodiment, the solid compositionscomprising a plurality of particles wherein the active ingredient oil isadsorbed on the surface of solid substance thereby enhancing the surfacearea of the oil on substrate particles. Such enhanced surface area ofthe oil can enhance absorption efficiency for each dose therebyimproving efficacy and reducing diarrhea at the same time. In oneembodiment, the solid composition can reduce the gastric stress andother side effects, enhance the therapeutic effect, and improve patientcompliance. In another embodiment, the solid composition can reducegastric and diarrheal tolerability issues, allow higher daily doses oftriheptanoin to be achieved and allow for better, and more completedigestion and absorption via the suspended stabilized particles in theGI tract with high surface area.

Triglycerides Solid Compositions

In the present invention, “triglyceride” refers to an ester derived fromglycerol and one or more fatty acids. The fatty acids can have a carbonchain that is optionally substituted alkyl, optionally substitutedalkenyl, or optionally substituted aryl.

“Alkyl,” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic monovalent hydrocarbonradical derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. The term “alkyl” includes “cycloakyl” asdefined herein below. Typical alkyl groups include, but are not limitedto, methyl; ethyl; propyls such as propan-1-yl, propan-2-yl (isopropyl),cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl(sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl(t-butyl), cyclobutan-1-yl, etc.; and the like. In some embodiments, analkyl group comprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 10 carbon atoms (C₁-C₁₀alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl) or 1 to 4 carbon atoms (C₁-C₄ alkyl). C₁-C₆alkyl is also known as “lower alkyl”.

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic monovalent hydrocarbonradical having at least one carbon-carbon double bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkene. The term “alkenyl” includes “cycloalkenyl” as defined hereinbelow. The group may be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like. In someembodiments, an alkenyl group comprises from 2 to 20 carbon atoms(C₂-C₂₀ alkenyl). In other embodiments, an alkenyl group comprises from2 to 10 carbon atoms (C₂-C₁₀ alkenyl). In still other embodiments, analkenyl group comprises from 2 to 6 carbon atoms (C₂-C₆ alkenyl) or 2 to4 carbon atoms (C₂-C₄ alkenyl). C₂-C₆ alkenyl is also known as “loweralkenyl”.

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 10 carbon atoms (C₆-C₁₀ aryl). In a specific embodiment, anaryl group comprises a phenyl group.

The term “substituted” specifically envisions and allows for one or moresubstitutions that are common in the art. However, it is generallyunderstood by those skilled in the art that the substituents should beselected so as to not adversely affect the useful characteristics of thecompound or adversely interfere with its function. Suitable substituentsmay include, for example, halogen groups, perfluoroalkyl groups,perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups,hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxygroups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups,arylalkyl or heteroarylalkyl groups, arylalkoxy or heteroarylalkoxygroups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,alkylcarbonyl groups, carboxyl groups, alkoxycarbonyl groups,alkylaminocarbonyl groups, dialkylamino carbonyl groups, arylcarbonylgroups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonylgroups, cycloalkyl groups, cyano groups, C₁-C₆ alkylthio groups,arylthio groups, nitro groups, keto groups, acyl groups, boronate orboronyl groups, phosphate or phosphonyl groups, sulfamyl groups,sulfonyl groups, sulfinyl groups, and combinations thereof. In the caseof substituted combinations, such as “substituted arylalkyl,” either thearyl or the alkyl group may be substituted, or both the aryl and thealkyl groups may be substituted with one or more substituents.Additionally, in some cases, suitable substituents may combine to formone or more rings as known to those of skill in the art.

The term “optionally substituted” denotes the presence or absence of thesubstituent group(s). That is, it means “substituted or unsubstituted”.For example, optionally substituted alkyl includes both unsubstitutedalkyl and substituted alkyl. The substituents used to substitute aspecified group can be further substituted, typically with one or moreof the same or different groups selected from the various groupsspecified above.

In some embodiments, the triglyceride is an ester derived from glyceroland three fatty acids independently selected from the odd-numberedcarbon fatty acids of C5, C7, C9, C11, C13, and C15. In someembodiments, the triglyceride is an ester derived from glycerol andthree fatty acids independently selected from phenylalkanoic acids andphenylalkenoic acids.

The present invention is based, in part, on the discovery thattriglycerides with one or more odd-numbered carbon fatty acids, such asC5, C7, C9, C11, C13, C15, and any combinations thereof, having a puritygreater than food grade can be formulated with a solid substance to forma solid composition. In one embodiment, the solid composition containsat least about 50% by weight the triglycerides, which can be in eithersolid or oil form prior to being formulated with the solid substance. Inone embodiment, the triglycerides are an oil prior to being formulatedwith the solid substance to form the solid composition.

In one embodiment, the present invention provides a solid compositioncomprising triglycerides with one or more odd-numbered carbon fattyacids as an active ingredient and a solid substance; wherein the activeingredient has purity greater than 98% and the one or more odd-numberedcarbon fatty acids are selected from the group consisting of C5, C7, C9,C11, C13, C15, and any combinations thereof; and the solid compositioncomprises at least about 50% by weight the triglycerides. In oneembodiment, the triglyceride is an ester derived from glycerol and threefatty acids independently selected from the odd-numbered carbon fattyacids of C5, C7, C9, C11, C13, and C15. In one specific embodiment, thetriglyceride is an ester derived from glycerol and three C7 fatty acids,i.e., triheptanoin. In one embodiment, the solid composition comprisestriglycerides with seven carbon fatty acids. In another embodiment, thesolid composition further comprises triglycerides with one or moreodd-numbered carbon fatty acids selected from the group consisting ofC5, C9, C11, C13, C15, and any combinations thereof. In anotherembodiment, the triglycerides with seven carbon fatty acids is atriheptanoin oil comprising greater than about 98% pure glyceroltriheptanoate as an active ingredient.

In some embodiment, the present invention provides a solid compositioncomprising triglycerides with one or more phenylalkanoic acids and/orphenylalkenoic acids as an active ingredient and a solid substance;wherein the active ingredient has purity greater than 95% and the solidcomposition comprises at least about 50% by weight the triglycerides. Inone embodiment, the triglyceride is an ester derived from glycerol andthree fatty acids independently selected from phenylalkanoic acids andphenylalkenoic acids. In one embodiment, the triglyceride is a compoundof formula (I):

wherein R₁, R₂, and R₃ are independently H,

and n is zero or an even number from 2-24 and in is an even number from2-24, provided that at least one of R₁, R₂, and R₃ is other than H. Inone embodiment, n and m are an even number from 2 to 24. In oneembodiment, n and m are 0, 2, 4, or 6. In one specific embodiment, thetriglyceride is an ester derived from glycerol and three phenylbutyrate,i.e., glycerol phenylbutyrate (e.g., RAVICTI®). Examples oftriglycerides with one or more phenylalkanoic acids and/orphenylalkenoic acids are further described in U.S. Pat. No. 5,968,979,the contents of which are hereby incorporated by reference in entiretyfor all purpose.

In one embodiment, the solid composition comprises at least about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, or about 90% of the triglycerides. In another embodiment, the solidcomposition comprises at least about 55%, about 60%, about 65%, about70%, about 75%, about 80%, or about 85% of the triglycerides. In onespecific embodiment, the solid composition comprises about 60% of thetriglycerides. In one specific embodiment, the solid compositioncomprises about 75%, about 80%, or about 85% of the triglycerides.

In some embodiments, the active ingredient in the solid composition hasa purity of about or at least about 95, 95.5, 96, 96.5, 97, 97.5, 97.6,97.7, 97.8, 97.9, 98, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.7, 98.8,98.9, 99.0, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% ormore, or any range derivable therein.

In one embodiment, the solid composition is in a powder form whichcomprises a plurality of particles, and each particle comprisestriglycerides with one or more odd-numbered carbon fatty acids as anactive ingredient adsorbed onto a solid substance. In one embodiment,the solid substance has a surface area of at least 20 m²/g.

In one embodiment, the solid substance comprises a solid carrier. Theterm “solid carrier”, as used herein, denotes any pharmaceuticallyacceptable solid material, which has a high surface area and does notadversely interact with the present triglycerides. By “high surfacearea”, it is meant that the solid carrier has a surface area of at least20 m²/g, or at least 30 m²/g, or at least 50 m²/g, or at least 70 m²/g,or at least 100 m²/g, or at least 150 m²/g, or at least 180 m²/g. In oneembodiment, the solid carrier can have surface areas of up to 200 m²/g,up to 400 m²/g, or up to 600 m²/g, or more. The surface area of thesubstrate can be measured using standard procedures, such aslow-temperature nitrogen adsorption, based on the Brunauer, Emmett, andTeller (BET) method, which is well known in the art.

In one embodiment, the particles have an average diameter of less thanabout 100 micron. In one embodiment, the particles have an averagediameter of less than about 90 micron, less than about 80 microns, lessthan about 70 microns, less than about 60 microns, less than about 50microns, less than about 40 microns, less than about 30 microns, lessthan about 20 microns, or less than about 10 microns. In anotherembodiment, the particles have an average diameter of less than about 9microns, less than about 8 microns, less than about 7 microns, less thanabout 6 microns, less than about 5 microns, less than about 4 microns,less than about 3 microns, less than about 2 microns, less than about1000 nm, less than about 900 nm, less than about 800 run, less thanabout 700 nm, less than about 600 nm, less than about 500 nm, less thanabout 400 nm, less than about 300 nm, less than about 290 nm, less thanabout 280 nm, less than about 270 nm, less than about 260 nm, less thanabout 250 nm, less than about 240 nm, less than about 230 nm, less thanabout 220 nm, less than about 210 nm, less than about 200 nm, less thanabout 190 urn, less than about 180 nm, less than about 170 nm, less thanabout 160 nm, less than about 150 nm, less than about 140 nm, less thanabout 130 nm, less than about 120 nm, less than about 110 nm, less thanabout 100 nm, less than about 90 nm, less than about 80 nm, less thanabout 70 nm, less than about 60 nm, less than about 50 nm, less thanabout 40 nm, less than about 30 nm, less than about 20 nm, less thanabout 10 nm, less than about 9 nm, less than about 8 nm, less than about7 nm, less than about 6 μm, or less than about 5 μm. The powder mayfirst be formed in the form of small particles ranging in size of fromabout 5 nm to about 1 micron, or from about 10 nm to about 50 nm, orfrom about 20 nm to about 100 nm. These particles may in turn formagglomerates ranging in size from about 10 nm to about 100 micron, or 20nm to about 100 micron, or about 50 nm to about 100 micron.

Examples of the solid carrier include fumed silica and inorganic oxides,such as SiO₂, TiO₂, ZnO₂, ZnO, Al₂O₃. MgAlSilicate, CaSilicate, Al(OH)₂,zeolites, and other inorganic molecular sieves; water insolublepolymers, such as cross-linked cellulose acetate phthalate, cross-linkedhydroxypropyl methyl cellulose acetate succinate, cross-linked polyvinylpyrrolidinone, (also known as cross povidone) microcrystallinecellulose, polyethylene/polyvinyl alcohol copolymer, polyethylenepolyvinyl pyrrolidone copolymer, cross-linked carboxymethyl cellulose,sodium starch glycolate, cross-linked polystyrene divinyl benzene; andactivated carbons, including those made by carbonization of polymerssuch as polyimides, polyacylonitrile, phenolic resins, celluloseacetate, regenerated cellulose, and rayon. In some specific embodiments,the solid carrier can be Cab-O-Sil, Neusilin, hypromellose acetatesuccinate (HPMCAS), Casein, or combinations thereof. In one embodiment,the solid carrier is fumed silica. Suitable fumed silica are availablefrom any major producers under various brand names, such as are Evonik(who sells it under the name Aerosil), Cabot Corporation (Cab-O-Sil),Wacker Chemie (HDK), Dow Corning, and OCI (Konasil).

In one embodiment, the solid substance further comprises one or moresustained release polymer. In one embodiment, the one or more sustainedrelease polymer comprises one or more pH dependent polymers. In oneembodiment, the pH dependent polymer is selected from a group consistingof a methyl acrylate-methacrylic acid copolymer, a cellulose acetatesuccinate, a hydroxy propyl methyl cellulose phthalate, a hydroxy propylmethyl cellulose acetate succinate (hypromellose acetate succinate), apolyvinyl acetate phthalate (PVAP), a methyl methacrylate-methacrylicacid copolymer, alginate and stearic acid, and any combinations thereof.

In one embodiment, the solid composition may further comprise one ormore additional pharmaceutically acceptable excipient, such as fillers,surfactants, and flavorants. Those excipients can be added to improvethe powder flowability, dissolvability, and taste.

“Pharmaceutically acceptable” refers to being suitable for use incontact with the tissues of humans and animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended usewithin the scope of sound medical judgment. “Excipient” denotes adiluent, adjuvant, vehicle or carrier with which the active ingredientis administered. Examples of the pharmaceutically acceptable excipientinclude, are not limited to a filler (or diluent), a binder, adisintegrant, a lubricant, or a combination thereof.

Fillers may be one or more compounds which are capable of providingcompactability and good flow. Examples of fillers includemicrocrystalline cellulose, starch, lactose, sucrose, glucose, mannitol,maltodextrin, sorbitol, dextrose, silicic acid, dibasic calciumphosphate, or a combination comprising at least one of the foregoingfillers. Exemplary lactose forms include lactose monohydrate, NF (FastFlo), lactose spray-dried monohydrate, and lactose anhydrous. Exemplarymicrocrystalline celluloses (MCC) include, for example, AVICEL® PH101and AVICEL® PH102, which are commercially available from FMC Biopolymer,Philadelphia, Pa.

Binders may be used to impart cohesive qualities to a formulation, forexample, a tablet formulation, and thus ensure that the tablet remainsintact after compaction. Examples of binders include starches (forexample, Starch 1500® or pregelatinized starch), alignates, gelatin,carboxymethylcellulose, sugars (for example, sucrose, glucose, dextrose,and maltodextrin), polyethylene glycol, waxes, natural and syntheticgums, polyvinylpyrrolidone, and cellulosic polymers (for example,microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, and hydroxyethyl cellulose) andcombinations comprising one or more of the foregoing binders.

Disintegrants are used to facilitate disintegration or “breakup” of acomposition, for example, a tablet, after administration. Examples ofdisintegrants include sodium starch glycolate, sodium croscarmellose(cross-linked carboxy methyl cellulose), crosslinkedpolyvinylpyrrolidone (PVP-XL), anhydrous calcium hydrogen phosphate,agar-agar, potato or tapioca starch, alginic acid, or a combinationcomprising one or more of the foregoing disintegrants.

A lubricant may be added to the composition for a minimum period of timeto obtain good dispersal. Examples of lubricants include magnesiumstearate, calcium stearate, zinc stearate, stearic acid, talc, glycerylbehenate, polyethylene glycol, polyethylene glycol, polyethylene oxide,sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodiumstearyl fumarate, DL-leucine, colloidal silica, or a combinationcomprising one or more of the foregoing lubricants.

If desired, the solid composition may optionally comprise small amountsof nontoxic auxiliary substances such as wetting or emulsifying agents,or pH buffering agents, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate,sodium lauryl sulfate, dioctyl sodium sulfosuccinate, andpolyoxyethylene sorbitan fatty acid esters.

In another embodiment of the present invention, the solid compositioncomprises one or more sustained release polymer. In one embodiment, thesolid substance comprises one or more sustained release polymer. By“sustained release polymer”, it is meant any polymer which can controlthe release of the active ingredient from the composition in such a wayto obtain the desired release profile. In one embodiment, the sustainedrelease polymer is a hydrophilic polymer. The term “hydrophilic polymer”refers to a polymer having a strong affinity for water and tending todissolve in, mix with, or be wetted by water. Examples of thehydrophilic polymer include, but are not limited to polyethylene oxide,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, methyl cellulose, polyacrylic acid, maltodextrin,pre-gelatinized starch, guar gum, sodium alginate, polyvinyl alcohol,chitosan, locust bean gum, amylase, any other water-swelling polymer,and a combination thereof. In another embodiment, the sustained releasepolymer is a film-forming, water insoluble polymer. Examples of thefilm-forming, water insoluble polymer include, but are not limited toethylcellulose, cellulose acetate, cellulose propionate (lower, mediumor higher molecular weight), cellulose acetate propionate, celluloseacetate butyrate, cellulose acetate phthalate, cellulose triacetate,poly(methyl methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate),poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenylmethacrylate), poly(methyl acrylate), poly(isopropyl acrylate),poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene),poly(ethylene) low density, poly(ethylene) high density,poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate),poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) orpolyurethane, or any other water insoluble polymer, or mixtures thereof.In another embodiment, the sustained release polymer is a film-forming,water soluble polymer. Examples of the film-forming, water solublepolymer include, but are not limited to polyvinyl alcohol,polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose and polyethylene glycol, Pluronic F108,Pluronic F127, Fluronic F68 or mixtures thereof. In one embodiment, thepresent solid composition comprises one or more the film-forming, waterinsoluble polymers. In one specific embodiment, the present solidcomposition comprises cellulose acetate.

In another embodiment, the sustained release polymer comprises one ormore pH dependent polymers. By “pH dependent polymers”, it is meantpolymers which are not soluble at the highly acidic pH but soluble inneutral to basic pH environment. Examples of pH dependent polymersinclude, but are not limited to, methyl acrylate-methacrylic acidcopolymers, cellulose acetate succinates, hydroxy propyl methylcellulose phthalates, hydroxy propyl methyl cellulose acetate succinates(hypromellose acetate succinates), polyvinyl acetate phthalates (PVAP),methyl methacrylate-methacrylic acid copolymers, alginate and stearicacid, and any combinations thereof. Furthermore, materials, such asfatty acids, waxes, shellac, plastics, and plant fibers, may also besuitable for pH dependent polymers.

The solid compositions as described herein can be used alone for variouspurposes, such as in treatment methods as described herein. In thisregard, the solid compositions can be pharmaceutically acceptable.

The present solid compositions can be formed by a spray-drying process.In one embodiment, the solid particles are formed by spray drying aspray suspension comprising the triglycerides with one or moreodd-numbered carbon fatty acids as an active ingredient and the solidsubstance. The spray suspension contains the triglycerides dissolved ina solvent and the solid substance suspended therein. Such spraysuspension is spray-dried to form a solid powder by rapidly removing thesolvent. The formed powder particles may have the triglycerides adsorbedon the surface of the solid substance or the triglycerides and the solidsubstance interspersed with one another to form a matrix. In anotherembodiment, the solid composition further comprises a sustained releasepolymer. For example, the solid particles may be formed by spray dryinga spray suspension comprising the triglycerides and the sustainedrelease polymer dissolved in a solvent with the solid substancesuspended therein. The spray suspension is spray-dried to form a solidpowder by rapidly removing the solvent.

In one embodiment, some powder formulations (with 75%, 80%, 85%, and 90%loading of triheptanoin on solid carrier) were prepared. Thetriheptanoin oil as described herein was first dissolved in acetone andthen mixed with the solid carrier, such as Cab-O-Sil, to form asuspension. The sustained release polymer, e.g., Eudragit, wasoptionally added. The resulting suspension was spray dried to obtain apowder. The spray dried powder is then dried further to reduce theamount of solvent (acetone) to a desirable level.

Triheptanoin Oil

In one embodiment, the triglyceride in the present solid composition isa triheptanoin oil. Triheptanoin oil as described herein comprisestriglycerides with seven carbon fatty acids. Triheptanoin, also known asglycerol triheptanoate, glycerol trienanthate, glyceryl triheptanoate,1,3-di(heptanoyloxy)propan-2-yl heptanoate, trienanthin, 1, 2,3-trienanthoylglycerol, and propane-1,2,3-triyl triheptanoate, is atriglyceride of the seven carbon (C7) fatty acid heptanoate (CASRegistry No. 620-67-7) and has the following structure:

Triheptanoin oil as described herein is of a purity or grade greaterthan food grade triheptanoin oil. In some embodiments, the triheptanoinoil is considered ultrapure pharmaceutical grade triheptanoin oil.

In one embodiment, the present triheptanoin oil has the generalproperties listed in Table 1:

Triheptanoin with Pharma- Physical and chemical property ceutical GradePurity Form Liquid Color Light yellow Cloud point <0° C. Flash point ca.220° C. Vapor pressure <0.01 hPa; 20° C. Relative Density ca. 0.96g/cm³; 20° C. Water solubility <0.01 g/l; 20° C. Partition coefficient(n-octanol/water) Log Pow: >3.0; glycerides of saturated C₇ fatty acidViscosity, dynamic ca. 20 mPa · s at 20° C. Refractive Index 1.4440 to1.4465

Typically, the total concentration of impurities in triheptanoin oil isless than the total concentration of impurities in food gradetriheptanoin oil. In some embodiments, food grade triheptanoin oil canhave a purity of about or at most about 95, 95.5, 96, 96.5, 97, or97.5%, or any range derivable therein.

In some embodiments, total impurities in triheptanoin oil amount to lessthan 5% w/w. In some embodiments, total impurities in triheptanoin oilamount to less than 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5% w/w orless, or any range derivable therein.

In one embodiment, triheptanoin oil comprises less than 2% w/w oftriglycerides esterified with acids other than C7 acids C2, C3, C4, C5,C6, C8, or C9 acids, or others, or combinations thereof (“non-C7triglycerides”)). In some embodiments, triheptanoin oil comprises lessthan 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7,0.6, 0.5, 0.4, 0.3, 0.2 or 0.1% w/w or less of non-C7 triglycerides, orany range derivable therein.

In one embodiment, triheptanoin oil comprises glycerol triheptanoate ofa purity of greater than 97.5%. In some embodiments, triheptanoin oilcomprises glycerol triheptanoate of a purity of about or at least about97.5, 97.6, 97.7, 97.8, 97.9, 98, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6,98.7, 98.8, 98.9, 99.0, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8,or 99.9% or more, or any range derivable therein.

In one embodiment, triheptanoin oil comprises less than 0.01% w/w ash.In some embodiments, triheptanoin oil comprises less than about 0.01,0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.001% w/wash or less, or any range derivable therein.

In one embodiment, triheptanoin oil comprises less than 0.04% w/w water.In some embodiments, triheptanoin oil comprises less than about 0.04,0.035, 0.03, 0.025, 0.02, 0.015, 0.01, 0.005, or 0.001% w/w water orless, or any range derivable therein.

In one embodiment, triheptanoin oil comprises less than 2.5% w/wglycerol. In some embodiments, triheptanoin oil comprises less than 2.5,2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.3, or 1.2% w/wglycerol or less, or any range derivable therein.

In one embodiment, triheptanoin oil comprises less than 1.5% w/wmonoheptanoate. In some embodiments, triheptanoin oil comprises lessthan 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6% w/wmonoheptanoateor less, or any range derivable therein.

In one embodiment, triheptanoin oil comprises less than 3.0% w/wdiheptanoate. In some embodiments, triheptanoin oil comprises less than3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 1.9, 1.8, or 1.7% w/wdiheptanoateor less, or any range derivable therein.

In one embodiment, triheptanoin oil comprises less than 2.5% w/wHexano-Diheptanoate. In some embodiments, triheptanoin oil comprisesless than 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.3, or1.2% w/w Hexano-Diheptanoateor less, or any range derivable therein.

In one embodiment, triheptanoin oil comprises less than 2.5% w/wHexanoic acid. In some embodiments, triheptanoin oil comprises less than2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.3, or 1.2% w/wglycerol or less, or any range derivable therein.

In some embodiments, the triheptanoin oil as described herein is acolorless oil of low viscosity and is odorless and tasteless.Triheptanoin oil as described herein is typically stored at roomtemperature and protected from light, and its stability can exceed 24months under such conditions.

In one embodiment, the present invention provides a solid compositioncomprises triheptanoin as the active ingredient; fumed silica; andcellulose acetate. In a further embodiment, the solid composition aplurality of solid particles, each particle comprising triheptanoinadsorbed onto a solid substance comprising fumed silica and celluloseacetate. In a further embodiment, the solid composition comprises, byweight of the composition, about 50% to about 80% of triheptanoin; about10% to about 30% of fumed silica; and about 10% to about 30% ofcellulose acetate. In another embodiment, the solid compositioncomprises, by weight of the composition, about 60% of triheptanoin;about 20% of fumed silica; and about 20% of cellulose acetate.

In one specific embodiment, the present triheptanoin oil has thecharacteristics listed in Table 2:

Parameter Specification Method IDENTITY Triheptanoate Comparable toreference Ph.Eur. 2.2.28 QUALITY Appearance Clear substance and Ph.Eur.2.2.1, 2.2.2. substance is not more method I intensely colored thanreference solution Y₃ Relative density  0.95-0.98 Ph.Eur. 2.2.5Refractive index 1.4440-1.4465 Ph.Eur. 2.2.6 Viscosity 15 mPa · s-23 mPa· s Ph.Eur. 2.2.9 PURITY Composition of fatty acids Heptanoic acid  >99% Ph.Eur. 2.4.22 Hexanoic acid Max. 0.8% method C All other, each<0.03% Saponification value 360 to 410 mg KOH/g Ph.Eur. 2.5.6 Acid valueMax. 0.2 mg KOH/g Ph.Eur. 2.5.1 Hydroxyl value Max. 10 mg KOH/g Ph.Eur.2.5.3 method A Peroxide value Max. 1.0 mg KOH/g Ph.Eur. 2.5.5 method AWater Max. 0.2% Ph.Eur. 2.5.12 Total ash Max. 0.1% Ph.Eur. 2.4.16 Heavymetals Max. 10 ppm Ph.Eur. 2.4.8 POTENCY/STRENGTH Triheptanoate 90% to110% Ph.Eur. 2.2.28

In one specific embodiment, the present triheptanoin oil has thecharacteristics listed in Table 3:

Parameter Specification Method IDENTITY Triheptanoate Comparable toreference Ph.Eur. 2.2.28 IR (infrared) Comparable to reference Ph.Eur.2.2.24 QUALITY Appearance Clarity and Opalescence Clear substancePh.Eur. 2.2.1 Color Substance is not more Ph.Eur. 2.2.2. intenselycolored than method I reference solution Y₃ PURITY Composition of fattyacids Heptanoic acid ≥99.0% Ph.Eur. 2.4.22 Hexanoic acid  ≤1.0% method CIndividual Unidentified ≤0.10% Impurities Impurities Glycerol  ≤1.0%Ph.Eur. 2.2.28 Monoheptanoate  ≤0.5% Diheptanoate  ≤1.5%Hexano-Diheptanoate  ≤1.0% Individual Unidentified  ≤0.5% ImpuritiesTotal Impurities  ≤5.0% Elemental Inpurities As ≤0.02 ppm Ph.Eur. 2.2.57or Cd ≤0.19 ppm 2.2.58 Pb ≤0.08 ppm Hg ≤0.12 ppm Acid value Max. 0.2 mgKOH/g Ph.Eur. 2.5.1 Water Max. 0.2% Ph.Eur. 2.5.12 Total ash Max. 0.1%Ph.Eur. 2.4.16 ASSAY Triheptanoate 95% to 103% Ph.Eur. 2.2.28

In certain specific embodiments, the triheptanoin oil has thecharacteristics listed in Table 4:

Parameter Example A Example B Triheptanoate Comparable Comparable toreference to reference Triheptanoate 99.0% 98.2% Impurities: Glycerolnot detectable not detectable Monoheptanoate not detectable notdetectable Diheptanoate 0.66% 0.62% Hexano-Diheptanoate 0.39% 0.40%Individual Unidentified 0.20% 0.18% Impurities (RRT* 1.258) (RRT 1.258)Total Impurities 1.25% 1.20% Elemental Inpurities As not detected notdetected Cd not detected not detected Pb not detected not detected Hgnot detected not detected *RRT: relative retention time.

Triheptanoin Oil Precursors and Manufacture of Triheptanoin Oil

Also provided herein are precursors to triheptanoin oil. In someembodiments, a precursor is n-heptanoic acid. n-Heptanoic acid has thefollowing structure:

n-Heptanoic: acid as described herein is of a purity or grade greaterthan food grade n-heptanoic acid. In some embodiments, purity of foodgrade n-heptanoic acid is between 90% and 98%. In some embodiments,purity of food grade n-heptanoic acid is between 95% and 98%. In someembodiments, purity of food grade n-heptanoic acid is between 95% and97.5%. In some embodiments, purity of food grade n-heptanoic acid has amaximum purity of 98, 97.9, 97.6, 97.5, 97.4, 97.3, 97.2, 97.1, 97.0,96.9, 96.8, 96.7, 96.6, 96.5, 96.4, 96.3%, 96.2, 96.1, 96.0, 95.9 95.8,95.7, 95.6, 95.5, 95.4, 95.3, 95.2, or 95.1%.

In some embodiments, n-heptanoic acid as described herein is consideredultrapure pharmaceutical grade n-heptanoic acid.

Typically, the total concentration of impurities in n-heptanoic acid isless than the total concentration of impurities in food graden-heptanoic acid. In some embodiments, total impurities in n-heptanoicacid amount to less than 4.0% w/w. In some embodiments, total impuritiesamount to less than about 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2,3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8,1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4,0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01%w/w or less, or any range derivable therein.

In one embodiment, n-heptanoic acid comprises less than 2% w/w oftriglycerides esterified with acids other than C7 acids (e.g., C2, C3,C4, C5, C6, C8, or C9 acids, or others, or combinations thereof (“non-C7triglycerides”)). In some embodiments, n-heptanoic acid comprises lessthan 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7,0.6, 0.5, 0.4, 0.3, 0.2 or 0.1% w/w or less of non-C₇ triglycerides, orany range derivable therein.

In one embodiment, an n-heptanoic acid composition comprises a sum of C7carboxylic acids having greater than 97% purity. In some embodiments,the purity is greater than 97, 97.1, 97.2, 97.3, 97.4, 97.5, 97.6, 97.7,97.8, 97.9, 98, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.7, 98.8, 98.9,99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8 or 99.9%, or more, orany range derivable therein. Compositions, such as pharmaceuticalcompositions, comprising n-heptanoic acid are also provided. Further,any composition comprising n-heptanoic acid can optionally be furtherdefined as a pharmaceutical composition.

Triheptanoin oil can be prepared from n-heptanoic acid as describedherein or a composition comprising n-heptanoic acid. For example,n-heptanoic acid can be esterified with glycerol to produce triheptanoinoil, such as in the presence of a basic catalyst and heat. In oneembodiment, an n-heptanoic acid composition comprises less than 3.0% w/wof 2-methylhexanoic acid. In some embodiments, the composition comprisesless than 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9,1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5,0.4, 0.3, 0.2, or 0.1% w/w 2-methylhexanoic acid, or less, or any rangederivable therein.

In one embodiment, an n-heptanoic acid composition comprises less than0.1% w/w water. In some embodiments, a composition comprises less than0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01% w/w ofwater or less, or any range derivable therein.

In one embodiment, an n-heptanoic acid composition comprises a carbonylcontent of less than 0.2% w/w. Carbonyl content measurements arewell-known in the art. In some embodiments, the carbonyl content is lessthan 0.15, 0.1, 0.05, or 0.01% w/w, or less, or any range derivabletherein.

In one embodiment, an n-heptanoic acid composition comprises an iodinenumber of less than 0.5%. Iodine number measurements are well-known inthe art. In some embodiments, the iodine number is less than 0.5, 0.4,0.3, 0.2, or 0.1% or less, or any range derivable therein.

In one embodiment, an n-heptanoic acid composition comprises less than0.2 mg/kg iron. In some embodiments, a composition comprises less than0.2, 0.15, 0.1, 0.05, or 0.01 mg/kg iron, or any range derivabletherein.

In one embodiment, a composition comprising n-heptanoic acid has aplatinum/cobalt color number of less than 0.25. Determination of theplatinum/cobalt color number is well-known in the art. In someembodiments, the platinum/cobalt color number is less than 0.25, 0.2,0.15, 0.1, or 0.05 or less, or any range derivable therein.

Therapeutic Treatments

Provided herein in some embodiments are methods of using the presentsolid composition for treatment. The solid composition can beadministered to a subject in need thereof in an amount effective totreat the subject.

For example, a subject may suffer from any one or more of the following:a fatty acid oxidation disorder or deficiency; adult polyglucosan bodydisease; a mitochondrial fat oxidation defect (e.g., relating tocarnitine palmitoyl transferase I, carnitine palmitoyl transferase II,carnitine acylcarnitine translocase, very long chain acyl-CoAdehydrogenase, triftinctional protein, long chain hydroxyacyl-CoAdehythogenase, multiple acyl-CoA dehydrogenase, short chain acyl CoAdehydrogenase, alpha glucosidase, brancher enzyme, debrancher enzyme,myophosphorylase, or phosphofructokinase); a glycogen storage disease(e.g., glycogen storage disease Type II); glucose transporter type 1(GLUT1) deficiency syndrome; or a mitochondrial myopathy. In someembodiments, triheptanoin oil as described herein or a pharmaceuticalcomposition comprising triheptanoin oil can be used to treat anycondition described in U.S. Pat. No. 8,106,093.

In another embodiment, a subject may suffer from urea cycle disorders(UCD), which include several inherited deficiencies of enzymes ortransporters necessary for the synthesis of urea from ammonia, includingenzymes involved in the urea cycle; or hepatic encephalopathy (HE),which a spectrum of neurologic signs and symptoms believed to resultfrom hyperammonemia, which frequently occur in subjects with cirrhosisor certain other types of liver disease. In some embodiments, glycerolphenylbutyrate as described herein or a pharmaceutical compositioncomprising glycerol phenylbutyrate can be used to treat theseconditions. Further details of methods of treatment using glycerolphenylbutyrate can be found in U.S. Pat. Nos. 8,404,215 and 8,642,012,the contents of which are hereby incorporated by reference in entiretyfor all purpose.

In one embodiment, the solid compositions can be administered to apatient directly in various dosage forms powders, granules, tablets,capsules, and the like) without mixing with food, drink, or othercomestible compositions. In another embodiment, the solid compositions,such as powders or granules, can be taken together with food, drink, orother comestible compositions by mixing the solid compositions into thefood, drink, or comestible compositions. The food, drink, or comestiblecompositions can be in any form including liquid, solid, semi-solid,foamy material, paste, gel, cream, lotion, and combinations thereof. Thesolid compositions can provide therapeutic effects while minimizegastric upset and gastrin release, and co-administration with food,drink, or other comestible compositions can enhance such tolerabilitybenefit. In addition, co-administration of food, drink, or othercomestible compositions with the solid composition can provide delayedand/or extended release of the active ingredients and thus allow lessfrequent dosing, longer term of energy exposure, and potentially higherefficiency in absorption from the GI tract. The delayed and/or extendedrelease characteristic of the solid composition can also beindependently achieved by including one or more sustained releasepolymers in the solid compositions as discussed above.

As used herein, the term “effective” (e.g., “an effective amount”) meansadequate to accomplish a desired, expected, or intended result. Aneffective amount can be a therapeutically effective amount. A“therapeutically effective amount” refers to the amount of an activeingredient that, when administered to a subject, is sufficient to effectsuch treatment of a particular disease or condition. The“therapeutically effective amount” will vary depending on, e.g., thedisease or condition, the severity of the disease or condition, and theage, weight, etc., of the subject to be treated.

In general, “treating” or “treatment” of any condition, disease ordisorder refers, in some embodiments, to ameliorating the condition,disease or disorder (i.e., arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In someembodiments “treating” or “treatment” refers to ameliorating at leastone physical parameter, which may not be discernible by the subject. Insome embodiments, “treating” or “treatment” refers to inhibiting thecondition, disease or disorder, either physically, (e.g., stabilizationof a discernible symptom), physiologically, (e.g., stabilization of aphysical parameter) or both. In some embodiments, “treating” or“treatment” refers to delaying the onset of a condition, disease, ordisorder.

EXAMPLES Example 1

Table 5 shows the high purity of exemplary triheptanoin oil samples andsolid samples comprising triheptanoin oil in accordance with the presentinvention.

Further, the stability of an exemplary solid composition (solid sample 2in Table 5) comprising triheptanoin oil was tested. Measurements wereconducted after storage at 25° C./60% RH (relative humidity) in doubleLDPE (low density polyethylene) bags in a 60 cc induction sealed HDPE(high density polyethylene) bottle and results are shown in Table 6.Measurements were also conducted after storage at 40° C./75% RH indouble LDPE bags in a 60 cc induction sealed HDPE bottle and results areshown in Table 7.

TABLE 5 Initial Purity Test Results Parameter Specification OIL Sample 1OIL Sample 2 SOLID Sample 1 SOLID Sample 2 SOLID Sample 3 ImpuritiesGlycerol ≤1.0% ND ND ND ND ND Monoheptanoate ≤0.5% ND ND ND ND NDDiheptanoate ≤1.5% 1.2% 0.7% 1.1% 1.1% 1.1% Hexano- ≤1.0% 0.4% 0.4% 0.4%0.4% 0.4% Diheptanoate Individual Unidentified ≤0.5% RRT 0.91: 0.06% RRT1.26: 0.20% RRT 0.91: 0.06% RRT 0.91: 0.06% RRT 0.91: 0.06% Impurities:RRT 1.05: 0.16% RRT 1.05: 0.16% RRT 1.05: 0.16% RRT 1.05: 0.16% RRT* (%)RRT 1.06: 0.17% RRT 1.06: 0.17% RRT 1.06: 0.17% RRT 1.06: 0.17% RRT1.07: 0.11% RRT 1.07: 0.11% RRT 1.07: 0.11% RRT 1.07: 0.11% RRT 1.25:0.06% RRT 1.25: 0.06% RRT 1.25: 0.06% RRT 1.25: 0.06% RRT 1.26: 0.23%RRT 1.26: 0.23% RRT 1.26: 0.23% RRT 1.26: 0.24% RRT 1.30: 0.10% RRT1.30: 0.10% RRT 1.30: 0.10% RRT 1.30: 0.10% RRT 1.36: 0.11% RRT 1.36:0.11% RRT 1.36: 0.11% RRT 1.36: 0.11% Total Impurities ≤5.0% 2.6% 1.3%2.6% 2.6% 2.6% RRT = relative retention time. ND = not detected.

TABLE 6 Stability Study Results for an exemplary solid compositionstored at 25° C./60% RH: Time points (months) Freshly Made (Five monthsParameter Specification before) 0 1 Appearance White to off ConformsConforms Conforms white powder Impurities Glycerol ≤1.0% ND ND NDMonoheptanoate ≤0.5% ND ND ND Diheptanoate ≤1.5% 1.1%  1.1%  1.1%Hexano-Diheptanoate ≤1.0% 0.4%  0.4%  0.4% Individual ≤0.5% RRT 0.91:0.06% RRT 0.91: 0.06% RRT 0.91: 0.05% Unidentified RRT 1.05: 0.16% RRT1.05: 0.16% RRT 1.05: 0.16% Impurities: RRT (%) RRT 1.06: 0.17% RRT1.06: 0.17% RRT 1.06: 0.17% RRT 1.07: 0.11% RRT 1.07: 0.11% RRT 1.07:0.11% RRT 1.25: 0.06% RRT 1.25: 0.06% RRT 1.25: 0.06% RRT 1.26: 0.23%RRT 1.26: 0.24% RRT 1.26: 0.23% RRT 1.30: 0.10% RRT 1.30: 0.10% RRT1.30: 0.09% RRT 1.36: 0.11% RRT 1.36: 0.11% RRT 1.36: 0.09% TotalImpurities ≤5.0% 2.6%  2.6%  2.5% Water NMT 5% NS 0.29% 0.35%Triheptanoate 90%-110%  99%  101%  100% Acetone ≤200 ppm <100 ppm NS NSRRT = relative retention time. NMT = not more than. ND = not detected.

TABLE 7 Stability Study Results for an exemplary solid compositionstored at 40° C./75% RH: Time points (months) Freshly Made (Five monthsParameter Specification before) 0 1 Appearance White to off- ConformsConforms Conforms white powder Impurities Glycerol ≤1.0% ND ND NDMonoheptanoate ≤0.5% ND ND ND Diheptanoate ≤1.5% 1.1%  1.1%  1.1%Hexano-Diheptanoate ≤1.0% 0.4%  0.4%  0.4% Individual ≤0.5% RRT 0.91:0.06% RRT 0.91: 0.06% RRT 0.91: 0.05% Unidentified RRT 1.05: 0.16% RRT1.05: 0.16% RRT 1.05: 0.16% Impurities: RRT (%) RRT 1.06: 0.17% RRT1.06: 0.17% RRT 1.06: 0.17% RRT 1.07: 0.11% RRT 1.07: 0.11% RRT 1.07:0.11% RRT 1.25: 0.06% RRT 1.25: 0.06% RRT 1.25: 0.06% RRT 1.26: 0.23%RRT 1.26: 0.24% RRT 1.26: 0.23% RRT 1.30: 0.10% RRT 1.30: 0.10% RRT1.30: 0.09% RRT 1.36: 0.11% RRT 1.36: 0.11% RRT 1.36: 0.10% Totalimpurities ≤5.0% 2.6%  2.6%  2.5% Water NMT 5% NS 0.29% 0.45%Triheptanoate 90%-110%  99%  101%   98% Acetone ≤200 ppm <100 ppm NS NSRRT = relative retent on time. NMT = not more than. ND = not detected.

Example 2

Single dose study of each arm with full pharmacokinetics (PK) profilethrough 48 hours post dose was performed to determined when metabolitesreturn to baseline (one week washout between each arm) as well as ifacute release of gastrin and cholesystokinin (CCK) hormones causespasmodic stomach contractions. Blood samples were collected from eacharm 0-90 min plus anytime outside this window if gastric distressobserved.

More specifically, animals (n=3/sex) were fasted prior to dose and fed 4hrs post dose. Blood samples for PK analysis of triheptanoin andmetabolites were collected pre-dose through 48 hrs post dose. As seen inthe multiple dose study (Example 3), there were no major differencesbetween males and females thus data was combined for all metabolites.

In FIGS. 1-21, animals were administered a single oral gavage dose levelof a triheptanoin oil sample (i.e., the oil) or exemplary solid samplescomprising triheptanoin oil in accordance with the present invention.The two exemplary solid compositions comprise 1) 60%:20%:20% oftriheptanoin oil: Cab-O-Sil: cellulose acetate (i.e., the Powder-ER);and 2) 80%:20% of triheptanoin oil: Cab-O-Sil (i.e., the Powder),respectively.

Triheptanoin and Heptanoic Acid

Triheptanoin is metabolized to heptanoic acid. The metabolite PKprofiles for the three samples are shown in FIGS. 1-4. Bio-modal peakswere observed for heptanopic acid on three arms. It is contemplatedthat: 1) the first peak may be when the triheptanoin hits the stomachand the second peak may be when the triheptanoin hits the duodenum; 2)fat soluble materials can be dissolved in the stomach but free heptanoinis absorbed in the duodenum (higher 2^(nd) peak for the powders); and 3)the cellulose acetate in the Powder-ER formulation delays delivery by˜one hour.

Energy Metabolites: Ketones

As seen in FIGS. 5-9, we observed comparable levels of ketones with oiltreatment and powder-ER treatment. Delivery of C4 ketones were fasterwith powders but also blunted by the powders. The ratio C4 ketone:C5ketone indicates the state of feeding; as this ratio increases itindicates that triheptanoin is being used as a source of calories.

Energy Metabolites: Aspartate

The levels of aspartate of the three samples are shown in FIGS. 10-12.We observed sustained release with the Powder-ER. It also showed a morefavorable effect on gluconeogenic precursors because of the delay inrelease. The levels of aspartate of the Oil and the powder return tobaseline at 8 hrs, while that of the powder-ER returns to baseline at 24hrs post dose.

Energy Metabolites: Glutamate

The levels of glutamate of the three samples are shown in FIGS. 13-15.When glutamate increases, the trend indicates that triheptanoin protectsagainst hypoglycemia. Triheptanoin increases the chemicals that can bemade into glucose. Livers in minipigs store gluconeogenic precursors inthe form of glutamate based on presence in the blood.

Alternative Metabolites

The metabolite PK profiles of alternative metabolites including pimelicacid, 3-hydroxypropionate and propionyl glycine are shown in FIGS.16-18. Pimelic acid and 3-hydroxypropionate production was not increasedwith the Powder-ER when compared to the oil. The levels were lower forthe powder. 3-hydroxyproprionate is a normal acid made by gut bacteria,but very dependent on the individual animal.

We have increased co-enzyme A activity by giving triheptanoin. Inaddition, the levels of average energy and alternative metabolites areshown in FIGS. 19-21.

Example 3

Multiple dose study was performed on the oil, the Powder and thePowder-ER as used in Example 2 and the results are shown below.

Powder Arm:

-   -   Day 1: Animal #6501 vomited ˜1 hour post dose    -   Day 3: Animal #6502 vomited    -   Day 3: Animal #6510 gastric distressed observed

Oil Arm:

-   -   Day 1: Animal 46501 vomited ˜3 hours post dose    -   Day 1: Animal 46516 vomited ˜3 hours post dose    -   Day 5: Animal #6509 gastric distressed observed

Powder ER Arm:

-   -   No vomiting or gastric distress observed

Heptanoic Acid Across Dose Groups

Overall, results as expected, the triheptanoin releases heptanoic acid.Referring to FIG. 22, triheptanoin was metabolized primarily in liver toC7 fatty acids and ketone bodies which distribute via circulation toother tissues to provide an energy source. There were no triheptanoinvalues in oil arm. All triheptanoin oil was converted to C7.

Trace amounts of triheptanoin were observed in powder arm. The powdermatrix may have caused a delay in the lipase action, this delay isslowing the release of C7. The Powder ER arm released slightly higherlevels of heptanoic acid than the powder arm but not as high as the oil.

Energy Metabolites

As seen in FIGS. 23 and 24, beta hydroxy levels rose 10-fold aboveresting state while ketone bodies did not increase from Day 1 to Day 7,which indicated no chance for ketosis.

Referring to FIGS. 25 and 26, we observed glutamic acid and asparticacid increased and the Powder had higher levels of both metabolites thanthe powder ER. Glutamic acid and aspartic acid are gluconeogenic aminoacids, and can represent a novel source of energy.

FIGS. 27-29 shows PK profiles of additional metabolites: A) pimelicacid, B) 3-hydroxypropionate, and C) propionylglycine following dosingon Day 1 and Day 7. The oil had the highest amount of pimelic acidcompared to the powders. 3-Hydroxypropionate was increasing in all 3groups but the powder-ER had the smallest increase and the lowestlevels. Propionylglycine was essentially zero for the oil and thepowder-ER but the powder dosing caused an increase. Overall, the PowderER produced the least amount of excess metabolites.

The PK profiles of all metabolites are shown in FIG. 30. The metabolitesinclude Triheptanoin, C4 (Hydroxy and Keto), C5 (Hydroxy and Keto),Heptanoic acid, Pimelic acid, Glutaric acid, Aspartic acid, Glutamicacid, Alanine and 3-Hydroxypropionic acid.

The results of the powder and the powder-ER as compared to that of theoil are shown in FIGS. 31-40. The Powder ER raised the C5-hydroxy levelsthe most of all the treatments, which indicates it's the most effectiveat delivering fatty acids to the cells. We observed differences betweenDays 1 and Day 7 for the powders. Day 7 levels were lower than Day 1,spike at 240 min on Day 1, which indicates that PK sampling can becarried out longer. The Powder-ER dosing resulted in lowest levels ofpimelic acid. The Powder had a higher release of aspartic acid than thePowder-ER. The Powder had higher levels of glutamic acid and alaninethan the Powder-ER. The Powder also had higher levels of3-Hydroxypropionate than the Powder-ER.

Following long-standing patent law convention, the terms “a”, “an”, and“the” refer to “one or more” when used in this application, includingthe claims.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive. It is specifically contemplated that any listingof items using the term “or” means that any of those listed items mayalso be specifically excluded from the related embodiment.

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which the present application belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the present application,representative methods and materials are herein described.

The patents listed herein describe the general skill in the art and arehereby incorporated by reference in their entireties for all purposesand to the same extent as if each was specifically and individuallyindicated to be incorporated by reference. In the case of any conflictbetween a cited reference and this specification, the specificationshall control. In describing embodiments of the present application,specific terminology is employed for the sake of clarity. However, theinvention is not intended to be limited to the specific terminology soselected. Nothing in this specification should be considered as limitingthe scope of the present invention. All examples presented arerepresentative and non-limiting. The above-described embodiments may bemodified or varied, without departing from the invention, as appreciatedby those skilled in the art in light of the above teachings.

1. A composition comprising an active ingredient, wherein the activeingredient is in a form of a triglyceride; wherein the triglyceride hasa purity greater than 95%; wherein the composition comprises thetriglyceride in at least about 50% by weight and the composition issubstantially free of glycerol; wherein the composition comprises waterin no more than 1.0% by weight; and wherein the composition comprisesglycerol in less than 1.0% by weight after about four weeks of exposureto about 40° C. at about 75% relative humidity when packaged in a sealedcontainer.
 2. The composition of claim 1, wherein the triglyceridecomprises one or more odd-numbered carbon fatty acids selected from thegroup consisting of C₅, C₇, C₉, C₁₁, C₁₃, C₁₅, and any combinationsthereof; and wherein the triglyceride has a purity greater than 98%. 3.The composition of claim 2, wherein the triglyceride is triheptanoinoil.
 4. The composition of claim 1, wherein the triglyceride comprisesone or more fatty acids selected from one or more phenylalkanoic acidsand/or phenylalkenoic acids.
 5. The composition of claim 4, wherein thetriglyceride has a structure of a compound of formula (I):

wherein R₁, R₂, and R₃ are independently

and n is zero or an even number from 2-24 and m is an even number from2-24.
 6. The composition of claim 5, wherein the triglyceride isglycerol phenylbutyrate.
 7. (canceled)
 8. The composition of claim 1,further comprising a solid carrier.
 9. (canceled)
 10. The composition ofclaim 8, wherein the solid carrier is selected from the group consistingof SiO₂, TiO₂, Al₂O₃, zeolites, Cab-O-Sil, and combinations thereof. 11.The composition of claim 1, comprising one or more sustained releasepolymers.
 12. The composition of claim 11, wherein the sustained releasepolymer is a film-forming, water insoluble polymer. 13.-14. (canceled)15. The composition of claim 11, wherein the one or more sustainedrelease polymer comprises one or more pH dependent polymers. 16.(canceled)
 17. The composition of claim 1, which is in form of a powder.18.-21. (canceled)
 22. A composition comprising a plurality of solidparticles, each particle comprising an active ingredient, wherein theactive ingredient is in a form of a triglyceride; wherein thetriglyceride is adsorbed onto a solid substance; wherein thetriglyceride has a purity greater than 95%; wherein the compositioncomprises the triglyceride in at least about 50% by weight and thecomposition is substantially free of glycerol; wherein the compositioncomprises water in no more than 1.0% by weight; and wherein thecomposition comprises glycerol in less than 1.0% by weight after aboutfour weeks of exposure to about 40° C. at about 75% relative humiditywhen packaged in a sealed container. 23.-41. (canceled)
 42. Thecomposition of claim 1, which further comprises a pharmaceuticallyacceptable excipient.
 43. The composition of claim 1, wherein thetriglyceride has a purity greater than 97% after about four weeks ofexposure to about 25° C. at about 60% relative humidity when packaged ina sealed container.
 44. The composition of claim 1, wherein thecomposition has a water content of no more than 0.35% by weight afterabout four weeks of exposure to about 25° C. at about 60% relativehumidity when packaged in a sealed container.
 45. The composition ofclaim 1, wherein the triglyceride has a purity greater than 97% afterabout four weeks of exposure to about 40° C. at about 75% relativehumidity when packaged in a sealed container.
 46. The composition ofclaim 1, wherein the composition has a water content of no more than0.45% by weight after about four weeks of exposure to 40° C. at about75% relative humidity when packaged in a sealed container.
 47. A methodof treating a disease, disorder, or condition in a subject comprisingorally administering to the subject a therapeutically effective amountof a composition of claim 1, wherein the disease, disorder, or conditionis selected from any one or more of the following: a fatty acidoxidation disorder or deficiency; adult polyglucosan body disease; amitochondrial fat oxidation defect; (a mitochondrial fat oxidationdefect relating to carnitine palmitoyl transferase; a mitochondrial fatoxidation defect relating to carnitine palmitoyl transferase II; amitochondrial fat oxidation defect relating to carnitine acylcarnitinetranslocase; a mitochondrial fat oxidation defect relating to very longchain acyl-CoA dehydrogenase; a mitochondrial fat oxidation defectrelating to trifunctional protein; a mitochondrial fat oxidation defectrelating to long chain hydroxyacyl-CoA dehydrogenase; a mitochondrialfat oxidation defect relating to multiple acyl-CoA dehydrogenase; amitochondrial fat oxidation defect relating to short chain acyl CoAdehydrogenase; a mitochondrial fat oxidation defect relating to alphaglucosidase; a mitochondrial fat oxidation defect relating to brancherenzyme; a mitochondrial fat oxidation defect relating to debrancherenzyme; a mitochondrial fat oxidation defect relating tomyophosphorylase; a mitochondrial fat oxidation defect relating tophosphofructokinase; a glycogen storage disease; (glycogen storagedisease Type II; glucose transporter type 1 (GLUT1) deficiency syndrome;or a mitochondrial myopathy.
 48. The method of claim 47, wherein thecomposition is co-administered with a food, drink, or comestiblecomposition.
 49. A method of treating a disease, disorder, or conditionin a subject comprising orally administering to the subject atherapeutically effective amount of a composition of claim 1, whereinthe disease, disorder, or condition is selected from urea cycledisorders (UCD) or hepatic encephalopathy (HE). 50.-63. (canceled) 64.The composition of claim 1, wherein the composition comprises glycerolin less than 0.5% by weight after about four weeks of exposure to about40° C. at about 75% relative humidity when packaged in a sealedcontainer.
 65. A composition comprising a triglyceride; wherein thetriglyceride has a purity greater than 97%; wherein the compositioncomprises the triglyceride in at least about 50% by weight and thecomposition is substantially free of glycerol; wherein the compositioncomprises water in no more than 1.0% by weight; and wherein thetriglyceride has a purity greater than 97% after about four weeks ofexposure to about 25° C. at about 60% relative humidity when packaged ina sealed container.